European Pharmacopoeia Activities on Control of Nitrosamines and other DNA-Reactive Impurities

An interesting article In Press in JPS:
Ph Eur.pdf (267.0 KB)
@Ulirose57 - Appreciate your efforts in sharing the Ph. Eur perspective pertaining to Nitrosamines in this article in JPS. Looking forward to reading the final published version.


Hi, @DAB.

Thank you for sharing the information. I’m interested in the following sentences in the conclusion.

These API-related nitrosamines might not be as reactive and mutagenic as small nitrosamines such as e.g., NDMA or NDEA. For these API-related nitrosamines a useful and harmonized regulatory strategy which tackles access to safe and available drugs and provides a clear regulatory concept industry can trust is still under debate among regulators. Tackling the risk of API-related nitrosamines in a scientifically sound way will be one of the main challenges with regards to nitrosamines for the next years and will require a clear guidance.

We are looking forward to a good solution, but it will take time…


Hi @Yosukemino
I feel the authors are referring to NDSRIs in this sentence.
Regulators expect MAHs to utilize Nitrosamine formation mitigation strategies that prevent formation of NDSRIs by including (a) inclusion of an antioxidant, such as vitamin C or vitamin E, in the formulation to inhibit the formation of nitrosamines (b) basifying the formulation as the formation of nitrosamines typically occurs under acidic conditions. FDA briefing documents that address these reformulation strategies should include a description of the formulation design strategy that is employed to minimize the formation of NDSRIs in the drug product, including supporting manufacturing information and, at a minimum, three months of accelerated stability data demonstrating control of NDSRI. For approved new drug applications (NDAs) and abbreviated new drug applications (ANDAs) that require reformulation as part of their mitigation strategy, bridging in vitro or in vivo bioequivalence studies will also be needed.
EMA has also outlined the various issues impacting on the drug product. These include reaction of amines within the APIs (or their impurities/degradants) with a nitrosating agent present in the excipients during manufacture or storage. Secondary amines appear to be particularly susceptible, although some tertiary amines have also been implicated.


Dear, @DAB

Thank you for your description. Formulation change is one of our exciting topics. The current situation regarding NDSRIs is unreasonably strict, and we need a solution. And we are not sure how the stability of drugs will be affected by formulation changes, even though the range of change is small. We will make sure the effect of formulation changes for each drug before the step 3 deadline.

Anyway, I look forward to new clear guidance.


You are welcome @Yosukemino

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